External topical administration is an important route for the administration of drugs in both systemic and topical disease treatment. For example, diseases of the skin, such as inflammatory diseases (e.g., acne), rashes, infection (e.g., microbial infection and parasitic infestation), and immune system reactions leading to rashes and/or infection, are typically treated via topical administration of a pharmaceutical active agent. Many drugs that may be useful for topical administration (e.g., antibiotics, anti-fungal agents, anti-inflammatory agents, anesthetics, analgesics, anti-allergic agents, corticosteroids, retinoids and anti-proliferative medications) are preferably administered in hydrophobic media, such as a petrolatum-based ointment or a cream, due to their increased stability in hydrophobic solvents. While the use of stabilizers, anti oxidants antimicrobial preservatives, buffers and the like in aqueous compositions to protect active or cosmetic agents is known, there are still disadvantages to formulating certain active agents in aqueous compositions, or even in compositions containing low amounts of polar solvents such as water (e.g., water in oil emulsions). For example, some active agents are known to be generally unstable or susceptible to isomerisation or to breakdown in the presence of water, resulting in loss of activity. Thus, in several cases, many drugs are more soluble or more stable in hydrophobic solvents; and therefore, the development of simple and elegant formulations to accommodate and stabilize active ingredients in a hydrophobic waterless or substantially waterless environment is desirable.
However, hydrophobic formulations, in particular ointments, also pose disadvantages to topical administration. For example, ointments often form an impermeable barrier. In the treatment of a topical wound, such a barrier would prevent the removal or draining of metabolic products and excreta from these wounds. Moreover, the efficacy of drugs formulated in ointments is compromised because of the difficulty for an active drug dissolved in an ointment-based carrier to pass through the barrier layer into the wound tissue. In addition, ointments and creams often do not create an environment for promoting respiration of wound tissue or normal respiration of the skin. An additional disadvantage of ointment formulations is the greasy feeling left following their topical application onto the skin, mucosal membranes and wounds.
Formulations based on hydrophobic media also include those based on oils or hydrophobic emollient vehicles. These formulations have a number of useful attributes making them suitable candidates for topical pharmaceutical and cosmetic compositions, including foamable compositions. They are inherently stable and inert which are clearly desirable characteristics. They are able to condition the skin and in appropriate amounts can form a barrier to skin moisture loss. By appropriate formulation they can act to improve drug delivery to the skin and yet remain resistant to being washed off. On the other hand, they are by their nature greasy materials and can be difficult to formulate particularly into a topical foamable composition that can deliver a substantially uniform and stable composition or foam that ameliorates or overcomes the look and feel of a greasy material, especially where that composition is waterless or substantially so. It is further a problem to incorporate into such a vehicle pharmaceutically effective amounts of one or more active pharmaceutical ingredients such that they are uniformly present throughout the formulation and are effectively delivered without the use of an alcohol in the formulation.
Foamable compositions offer advantages over ointments and creams for topical administration of pharmaceuticals. While hydrophobic foamable compositions are known, it is far from simple or obvious to produce hydrophobic waterless foamable compositions that when released produce foams of quality suitable for pharmaceutical or cosmetic application. On a further level, having realized a carrier that will produce a hydrophobic waterless foam of quality there is an additional difficulty to be overcome, namely how to adapt the formula and achieve a uniform formulation, which can accept a range of various active pharmaceutical and cosmetic agents such that the composition and active agent are stable and the foam produced remains of quality. Specifically, one of the challenges in preparing such waterless or substantially waterless foamable compositions is ensuring that the active pharmaceutical or therapeutic agent does not react, isomerize or otherwise break down to any significant extent during is storage and use. Particularly, there remains an unmet need for improved, easy to use, stable and non-irritating foam formulations, with unique therapeutic or beneficial properties containing a stable or stabilized active pharmaceutical or cosmetic agent.
Silicones are hydrophobic substances that offer unique cosmetic properties. They are tasteless, essentially odorless, non-greasy and non-stinging; they are used as a base fluid in many personal care products, with excellent spreading and easy rubout and lubrication properties. Volatile silicone compounds are a specific class of silicones, used in dermal formulations to condition the skin, while reducing the greasy feel of other oils in the formulation. However, one of the principal hindrances to the use of silicones in foam formulations is their known antifoaming effect, especially when included in the formulation in substantial quantities. More specifically, silicones are known for being efficient foam control agents and can prevent foam formation or cause foam to collapse rapidly. Silicone fluids can, for example, enter into the foam lamella and displace the foam stabilizing surfactants from the interphase. The foam lamellas are therefore destabilized and burst resulting in foam collapse. Thus, silicones are essentially contra-indicated for the preparation of foamable carriers and compositions. Nevertheless, because of the favorable properties of silicones, there is still an unmet need to develop foamable formulations incorporating silicone that can produce easy to use good quality foam, especially in substantial quantities.
In general terms foam formed from hydrophobic waterless or substantially waterless compositions may by their inherent nature be less firm or inherently weaker than water based emulsion compositions. Thus, not only are silicones inherently unsuitable for forming foamable compositions but it may additionally go against the grain to try and use them in waterless compositions.
US Patent Publication No. 2008/0031908 describes an aerosol product containing an oily composition containing at least one oil, and at least one hydrocarbon compound (notably, a paraffin or a fatty acid amide) having a melting point greater than or equal to 30° C. (i.e., a solid at room temperature), the compound being in the form of solid particles and one or more propellants. Hydrocarbon solid particles were required to provide a fine bubble, stable foam.
US Patent Publication No. 2005/0287081 (corresponding to International Patent Publication No. WO 2006/031271) describes a topical pharmaceutical aerosol foam containing high levels of liquid silicones to enhance cosmetic elegance, containing five essential ingredients: (1) a lipophilic compound or combinations of lipophilic compounds; (2) a liquid silicone or a combination of liquid silicones; (3) a foaming agent, which is selected from the group consisting of mono, di, tri esters of sorbitol and fatty acids; (4) an active agent; and (5) a propellant. The formulations described in the publication contain less than 60% liquid oil and significant levels of liquid silicone, indicating that foamable compositions containing very high levels of liquid oil were not achieved. Notably, the foam product of the formulations described in US 2005/0287081 is prone to collapse quickly as illustrated below in the Examples, which is also undesirable for a topical foam formulation.
U.S. Pat. No. 3,770,648 teaches that solid silicone resin must be present in quantities to produce a quick breaking anhydrous foam.
Foams are complex dispersion systems which do not form under all circumstances. Slight shifts in foam composition, such as by the addition of active ingredients, may destabilize the foam. Foams are very complex and sensitive systems and are not formed at will. Mere addition of basic ingredients like oil, surfactant and propellant is far from sufficient to produce foams of quality that are homogenous, stable, breakable upon mechanical force and can be used to provide a shelf stable pharmaceutical or cosmetic composition. Small deviations may lead to foam collapse. Much consideration needs to be given to facilitate the introduction of an active agent, such as examining compatibility and non reactivity with the various excipients and container and determining shelf life chemical stability.
Neubourg (US 2006/0099151), for example, notes that the stability of foam is strongly dependent on the specific composition of the foam forming components, so that even small deviations in the composition may lead to a collapse of the foam. Gordon et al. (U.S. Pat. No. 3,456,052). also teaches that one cannot generate a good quality foam by simply adding a propellant to a mixture of components:
The term “foam” is a general term that encompasses a range of substances. Accordingly, the context in which “foam” is discussed must be examined carefully. The type and quality of the foam is of critical importance. There are many different types of foams and within each foam type there are many levels of qualities. For example, the froth on the head of beer, lather of shampoo, and lather of shaving cream have been loosely described as foam but all are different from one another. At one end of the cosmetic or pharmaceutical foam spectrum the foam can be long lasting and essentially not readily breakable like shaving foams. At the other end of the spectrum the foam can be quick breaking and collapses upon release.
Thermolabile foams are an example of type of quick breaking foam. They can contain significant amounts of thermolabile substances that aid their collapse upon being exposed to an increased temperature for example when applied to a body surface at 37 C. Upon being exposed to the higher temperature they collapse rapidly. Examples are foam formulations that comprise significant amounts of volatile solvents.
Breakable foam is a specialized type of foam. It is a low density foam that is stable on release at least in the short time span of several minutes, which facilitates application to a target area; but can break readily upon the application of shear force such as gentle rubbing to spread easily over a target surface. It is not thermolabile (and does not melt at skin temperature) and nor does it display late or long delayed expansion over minutes. In some embodiments, the compositions described herein produce breakable foams.
Some foams expand slowly whilst others do so quickly. Some foams foam immediately and some demonstrate delayed foaming. Some require mechanical lathering and some expulsion by propellant. Whilst they all fall under the so called term “foam” and may appear to have some common ingredients the results and properties of these products are different.
A suitable foamable formulation for a particular application may present challenges at several levels. For example, a foam formulation may require a stable pre foam formulation; a stable pre foam propellant formulation (e.g., a foamable carrier) and ultimately delivery an effective measured amount of active agent to a target. Each of these objectives poses its own unique challenges.
The pharmaceutical and cosmetic foams discussed herein are generated in general terms by manufacturing a suitable foamable carrier composition and loading the carrier in a pressurized valved canister with an appropriate propellant. Upon expelling the canister contents a foam can be released. The type, nature and quality of the foam depends inter alia on the carrier composition, the active agent, the propellant and the method of manufacture and storage. Making a stable (physically and chemically) formulation that can be stored in a canister with a propellant that remains stable and can produce a breakable foam of quality on release is far from trivial.
An additional difficulty frequently encountered with propellant foams is their inability to dispense a uniform application of the medically active ingredient throughout the use of the entire aerosol container. This is particularly due to the fact that the active material is not stably dispersed in the foamable composition so that it will have a tendency to settle to the bottom. Further, the dispersed material will sometimes clog the spray dispensing valve to further interfere with the uniform dispensing of the medicament.